Molecular mechanisms which regulate the intracellular bioavailability of metals such as lead and cadmium have been studied in both mammals and marine invertebrates. High affinity cytosolic lead-binding proteins PbBP of 63,000 (63K) and 11,500 (11.5K) daltons from kidneys of rats have been partially purified by gel and anion exchange chromatography, electrophoresis, and sucrose density gradient analysis. These molecules were found to exhibit dissociation constants (Kd) for lead of 10 to the -8M. Sucrose density gradient analysis (SDGA) of these molecules showed sedimentation coefficients of 2S and 4.6S for the 11.5K and 63K dalton PbBP, respectively. Competitive binding studies on sucrose density gradiantes with cytosol showed displacement of 203Pb by PbII, CdII and ZnII ions but not CaII ions. Cell-free nuclear translocation studies showed both time- and temperature-dependent uptake of 203Pb from kidney cytosol and KC1 extraction of these nuclei followed by SDGA indicated the presence of one saturable peak with a sedimentation coefficient of 2S. CdII and ZnII ions effectively blocked the nuclear uptake of 203Pb. The data indicate that these high affinity PbBP, which act as the initial cytosolic ligands for Pb in the kidney, are capable of mediating the intranuclear translocation of Pb and that this process is competitively blocked by CdII and ZnII. The 11.5K dalton protein, but not the 63K protein, was also found to regulate the inhibitory effects of Pb on the heme biosynthetic pathway enzyme Delta-aminolevulinic acid dehydratase (ALAD). Reversal of Pb-induced inhibition of hepatic ALAD activity was dependent on the concentration of 11.5K dalton PbBP added to the reaction mixture. Kinetic analysis of either hepatic or renal ALAD activity indicated a non-competitive inhibition pattern. Addition of the semi-purified 11.5K dalton PbBP to the assay mixture markedly reduced the inhibitory effects of Pb on the Vmax of the enzyme from either tissue. The data indicate that the 11.5K dalton protein confers partial resistance to Pb inhibition of liver ALAD in vitro and suggests a similar role for this protein in kidney with respect to the resistance of renal ALAD to Pb inhibition.